US6132768A - Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors - Google Patents

Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors Download PDF

Info

Publication number
US6132768A
US6132768A US08/498,391 US49839195A US6132768A US 6132768 A US6132768 A US 6132768A US 49839195 A US49839195 A US 49839195A US 6132768 A US6132768 A US 6132768A
Authority
US
United States
Prior art keywords
reversible
proton
pyridine
active ingredient
pump inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/498,391
Inventor
George Sachs
Rango Dietrich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Priority to US08/498,391 priority Critical patent/US6132768A/en
Assigned to BYK GULDEN CHEMISCHE FABRIK GMBH reassignment BYK GULDEN CHEMISCHE FABRIK GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DIETRICH, RANGO, SACHS, GEORGE
Priority to PCT/EP1996/002893 priority patent/WO1997002021A1/en
Priority to ES96924850T priority patent/ES2192227T3/en
Priority to DE69626117T priority patent/DE69626117T2/en
Priority to AT96924850T priority patent/ATE232091T1/en
Priority to CA002225628A priority patent/CA2225628C/en
Priority to AU65175/96A priority patent/AU711577B2/en
Priority to DK96924850T priority patent/DK0841904T3/en
Priority to PT96924850T priority patent/PT841904E/en
Priority to EP96924850A priority patent/EP0841904B1/en
Priority to SI9630596T priority patent/SI0841904T1/en
Priority to JP9504812A priority patent/JPH11508578A/en
Priority to HK98112158A priority patent/HK1010835A1/en
Publication of US6132768A publication Critical patent/US6132768A/en
Application granted granted Critical
Assigned to ALTANA PHARMA AG reassignment ALTANA PHARMA AG CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH
Priority to CY0400048A priority patent/CY2460B1/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to oral pharmaceutical compositions in pellet or tablet form for reversible proton pump inhibitors for combined use with antimicrobially-active ingredients for the treatment of disorders caused by Helicobacter.
  • Control of the microbe Helicobacter pylori which is thought to be responsible for certain gastric disorders, by combined use of an antimicrobially-active ingredient which is active against Helicobacter pylori and of an agent which reduces gastric acid has been regarded as the method of choice for some time.
  • Irreversible proton pump inhibitors are substances which covalently, and thus irreversibly, bind to the enzyme which is responsible for acid secretion in the stomach, the H + /K + ATPase.
  • irreversible proton pump inhibitors which essentially have a common basic chemical structure (pyridinylmethylsulfinylbenzimidazoles)
  • reversible H + /K + ATPase inhibitors which have different basic chemical structures and which, as the name indicates, reversibly bind to the enzyme responsible for gastric acid secretion.
  • reversible proton pump inhibitors in connection with the present invention.
  • Reversible proton pump inhibitors are disclosed, for example, in the documents JP-A-3031280, DE-A-3917232, EP-A-0399267, EP-A-0387821, JP-A-3031280, JP-A-2270873, EP-A-0308917, EP-A-0268989, EP-A-0228006, EP-A-0204285, EP-A-0165545, EP-A-0125756, EP-A-0120589, EP-A-0509974, DE-A-3622036, EP-A-0537532, EP-A-0535529, JP-A-3284686, JP-A-3284622, U.S. Pat. No.
  • EP-A-0261912 WO-A-9114677, WO-A-9315055, WO-A-9315071, WO-A-9315056, WO-A-9312090, WO-A-9212969, WO-A-9118887, EP-A-0393926, EP-A-0307078, U.S. Pat. No.
  • EP-A-0266890 WO-A-9414795, EP-A-0264883, EP-A-0033094, EP-A-0259174, EP-A-0330485, WO-A-8900570, EP-A-0368158, WO-A-9117164, WO-A-9206979, WO-A-9312090, WO-A-9308190, WO-A-9418199, DE-A-3011490, U.S. Pat. No. 4,464,372, EP-A-0068378 and WO-A-9424130.
  • an antimicrobially-active ingredient on Helicobacter is surprisingly enhanced by administering a reversible proton pump inhibitor in slow-release dosage form (extended release form). It must be regarded as particularly surprising that, in addition, administration of the slow-release reversible proton pump inhibitor results in the onset of action taking place significantly faster than on administration of a non-slow-release reversible proton pump inhibitor. The duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.
  • the invention thus relates to oral pharmaceutical compositions in pellet or tablet form for reversible proton pump inhibitors for combined use with antimicrobially-active ingredients for the treatment of disorders caused by Helicobacter, wherein the reversible proton pump inhibitor is present at least partly in slow-release form.
  • Reversible proton pump inhibitors are, for the purpose of the present invention, those active ingredients which reversibly bind to the enzyme responsible for gastric acid secretion, H + /K + ATPase. Examples of reversible proton pump inhibitors are enumerated in the previously-noted documents.
  • Examples of reversible proton pump inhibitors are, e.g., 8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (hereinafter B9401-011), 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2 methylimidazo[1,2-a]pyridine, 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine, 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[
  • Reversible proton pump inhibitors can, in this connection, be present as such, in the form of their salts and/or their solvates (e.g. hydrates), etc.
  • Particularly suitable salts are (because all reversible proton pump inhibitors are substances with a basic reaction) all acid-addition salts.
  • the pharmacologically-acceptable salts of inorganic and organic acids customarily used in pharmaceutical technology, including water-soluble and water-insoluble acid-addition salts with acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid and 3-hydroxy-2-naphthoic acid, the acids being used in the preparation of the salt in a ratio of amounts which are equimolar or different therefrom---depending on whether the acid is mono- or polybasic and depending on the
  • suitable antimicrobially-active ingredients active against Helicobacter pylori
  • active ingredients include, for example, bismuth salts (such as bismuth subcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such as nitrofurazone, nitrofurantoin or furazolidone), metronidazole, tinidazole, nimorazole or antibiotics.
  • antibiotics which may be mentioned in this connection are, arranged according to particular classes of active ingredient: aminoglycosides, such as gentamicin, neomycin, kanamycin, amikacin or streptomycin; macrolides, such as erythromycin, azithromycin, clarithromycin, clindamycin or rifampicin; penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillin or amoxicillin; polypeptides, such as bacitracin or polymyxin; tetracyclines, such as tetracyline, chlorotetracycline, oxytetracycline, minocycline or doxycycline; carbapenems, such as imipenem, loracarbef, meropenem or panipenem; cephalosporins, such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxime proxet
  • a plurality of antimicrobially-active ingredients for example the combination of a bismuth salt and/or tetracycline with metronidazole, or the combination of amoxicillin or clarithromycin with metronidazole.
  • a reversible proton pump inhibitor together with a plurality of antimicrobially-active ingredients, for example with the combination of a bismuth salt and/or tetracycline with metronidazole, or with the combination of amoxicillin or clarithromycin or with metronidazole.
  • the dosage of the active ingredients depends greatly on the nature of the reversible proton pump inhibitor used and of the antimicrobially-active ingredient(s) used.
  • a typical dosage of a reversible proton pump inhibitor as disclosed, for example, in WO-A-9418199 can be regarded as a daily dose of from about 0.01 to about 20, preferably from 0.05 to 5, and in particular from 0.1 to 1.5, mg/kg of body weight, where appropriate in the form of a plurality of single doses.
  • Penicillins such as amoxicillin, are administered in a daily dose of from about 5 to 40, preferably from 10 to 20, mg/kg of body weight.
  • Antimicrobially-active ingredients which may be emphasized are erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline, doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin, of loxacin and pefloxacin.
  • Clarithromycin and amoxicillin may be mentioned as antimicrobially-active ingredients which should be particularly emphasized.
  • Combined administration means fixed and, in particular, free combinations, i.e. the slow-release reversible proton pump inhibitor and the antimicrobially-active ingredient are present together in one dosage unit, or slow-release reversible proton pump inhibitor and antimicrobially-active ingredient, which are present in separate dosage units, are administered in direct succession or at a relatively large time interval; a relatively large time interval means within a time span of up to a maximum of 24 hours. For use as separate dosage units, these are preferably made available together in one pack.
  • the two dosage units are packed together in blister packs which are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the times for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
  • a dosage unit means, in particular, those medicinal dosage forms in which slowing or extending of reversible proton pump inhibitor release is achieved with as few problems as possible.
  • These include, in particular, tablets, coated tablets or pellets, and microtablets in capsules, with the dosage form advantageously being designed so that the two active ingredient components (reversible proton pump inhibitor on the one hand and antimicrobially-active ingredient on the other hand) are released, or made available effectively for the body, in such a way that an optimal active-ingredient profile (and thus action profile) is achieved.
  • various types and degrees of retarding release may be used to ensure a reversible proton pump inhibitor plasma level which persists as long as possible and is sufficient for raising pH.
  • the pharmaceutical formulation of the antimicrobially-active ingredient(s) is carried out in a manner which is familiar per se to the skilled worker for the individual active ingredients.
  • the rapid release of part of the reversible proton pump inhibitor and retarding release of another part is optionally achieved, for example, by layered tablets or multilayer tablets, in which part of the reversible proton pump inhibitor is present in an outer coating in a form without slowing release; this is followed by another coating containing the antimicrobially-active ingredient and then the core with the reversible proton pump inhibitor whose release is slowed in a suitable manner.
  • oral pharmaceutical compositions according to the invention are distinguished from the prior art by controlled release of active ingredients and increased stability.
  • Suitable binder is, in particular, polyvinylpyrrolidone in various degrees of polymerization.
  • lubricants and nonstick agents are higher fatty acids and their alkali-metal and alkaline-earth-metal salts, such as calcium stearate.
  • Suitable tablet disintegrants are, in particular, chemically-inert agents.
  • Preferred tablet disintegrants include cross-linked polyvinylpyrrolidone, crosslinked sodium carboxymethylcelluloses and sodium starch glycolate.
  • suitable film polymers in respect of the water-insoluble release-slowing intermediate layer(s) to be applied to the pellet or tablet core, include ethylcellulose, polyvinyl acetate, Eudragit® RS, Eudragit® RL, etc.
  • the release rate can be controlled not only by incorporating suitable water-soluble pore formers, such as PEG, lactose, mannitol, sorbitol, HPMC, etc., but also by the thickness of the coating layer applied.
  • the solvents or dispersants used for the release-controlling polymer dispersion are non-aqueous organic solvents, such as alcohols, ketones, halogenated hydrocarbons or mixtures of such solvents.
  • Suitable polymers for the enteric coating are methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymer (Eudragit® L) or cellulose derivatives, such as carboxymethylethylcellulose (CMEC, Duodcel), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinyl acetate phthalate, to which it is also possible to add, if desired, plasticizer (such as propylene glycol) and/or other additives and ancillary substances (e.g. buffer base, such as, preferably, aluminum hydroxide; or pigment).
  • the layers are applied in conventional ways using equipment customary for these purposes.
  • the combined use according to the invention of a slow-release reversible proton pump inhibitor with an antimicrobially-active ingredient meets all the requirements for a pharmaceutical product or combination pharmaceutical product for the treatment of gastric disorders attributable to the microbe, Helicobacter pylori.
  • the particular advantages connected with the combined use of the slow-release drug form with an antimicrobially-active ingredient which may be mentioned are: the rapid onset of action with pH values as far as neutral in the lumen of the stomach and in the wall of the stomach and an optimal displaying of the effect of the antimicrobially-active ingredient.
  • the short duration of treatment which can be achieved increases the compliance, which is extremely important for antibiotic treatments.
  • a) is mixed with b), c) and part of d).
  • a paste is prepared with the remainder of d).
  • the latter is used for granulation of the powder mixture in a suitable mixer.
  • the granules are dried in a drying oven or fluidized bed.
  • e) is added to the dried granules, and the granules are compressed in a suitable tabletting machine.
  • the tablet cores obtained under I are coated to an adequate layer thickness with the suspension obtained above in suitable apparatus.
  • the tablet cores obtained under I are coated to a sufficient layer thickness with the thus-obtained dispersion in suitable apparatus.
  • a) is sprayed with an aqueous solution of b) and c) in a fluidized bed (Wurster method).
  • d), e), f) are successively dissolved in 4 liters of purified water and sprayed onto 900 g of the pellets obtained under I in a fluidized bed (Wurster method).
  • a release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
  • a) and b) are premixed dry and subsequently moistened to a paste-like consistency with a solution of Na carboxymethylcellulose in water in a conventional kneader or high-speed mixer.
  • the resulting composition is then extruded and shaped into pellets by the extruder/rounder method familiar to the skilled worker.
  • the moistened pellets are dried in suitable equipment (drying oven, fluidized bed, etc.).
  • the release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.

Abstract

An oral pharmaceutical composition of a reversible proton pump inhibitor in pellet or tablet form, wherein the reversible proton pump inhibitor is at least partly in slow-release form, is distinguished, on combined administration with an antimicrobially-active ingredient, by an enhanced action of rapid onset against disorders caused by Helicobacter.

Description

RELATED APPLICATION
This application is related to Applicants' concurrently-filed application U.S. Ser. No. 08/498,386 filed Jul. 5, 1995, now U.S. Pat. No. 5,945,124.
FIELD OF THE INVENTION
The present invention relates to oral pharmaceutical compositions in pellet or tablet form for reversible proton pump inhibitors for combined use with antimicrobially-active ingredients for the treatment of disorders caused by Helicobacter.
PRIOR ART
Control of the microbe Helicobacter pylori, which is thought to be responsible for certain gastric disorders, by combined use of an antimicrobially-active ingredient which is active against Helicobacter pylori and of an agent which reduces gastric acid has been regarded as the method of choice for some time.
Besides inhibitors of gastric acid secretion of the H2 receptor antagonist type, in recent times use has been made, with more or less success, of compounds of the class of so-called irreversible proton pump inhibitors (such as pantoprazole, omeprazole or lansoprazole). Irreversible proton pump inhibitors are substances which covalently, and thus irreversibly, bind to the enzyme which is responsible for acid secretion in the stomach, the H+ /K+ ATPase.
Besides so-called irreversible proton pump inhibitors, which essentially have a common basic chemical structure (pyridinylmethylsulfinylbenzimidazoles), there are the so-called reversible H+ /K+ ATPase inhibitors which have different basic chemical structures and which, as the name indicates, reversibly bind to the enzyme responsible for gastric acid secretion. These are called reversible proton pump inhibitors in connection with the present invention. Reversible proton pump inhibitors are disclosed, for example, in the documents JP-A-3031280, DE-A-3917232, EP-A-0399267, EP-A-0387821, JP-A-3031280, JP-A-2270873, EP-A-0308917, EP-A-0268989, EP-A-0228006, EP-A-0204285, EP-A-0165545, EP-A-0125756, EP-A-0120589, EP-A-0509974, DE-A-3622036, EP-A-0537532, EP-A-0535529, JP-A-3284686, JP-A-3284622, U.S. Pat. No. 4,833,149, EP-A-0261912, WO-A-9114677, WO-A-9315055, WO-A-9315071, WO-A-9315056, WO-A-9312090, WO-A-9212969, WO-A-9118887, EP-A-0393926, EP-A-0307078, U.S. Pat. No. 5,041,442, EP-A-0266890, WO-A-9414795, EP-A-0264883, EP-A-0033094, EP-A-0259174, EP-A-0330485, WO-A-8900570, EP-A-0368158, WO-A-9117164, WO-A-9206979, WO-A-9312090, WO-A-9308190, WO-A-9418199, DE-A-3011490, U.S. Pat. No. 4,464,372, EP-A-0068378 and WO-A-9424130.
Combined use of reversible proton pump inhibitors with antimicrobially-active ingredients has a good effect against Helicobacter in vitro. However, the clinical effect achieved with this combined use is disappointing.
SUMMARY OF THE INVENTION
The action of an antimicrobially-active ingredient on Helicobacter is surprisingly enhanced by administering a reversible proton pump inhibitor in slow-release dosage form (extended release form). It must be regarded as particularly surprising that, in addition, administration of the slow-release reversible proton pump inhibitor results in the onset of action taking place significantly faster than on administration of a non-slow-release reversible proton pump inhibitor. The duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.
The invention thus relates to oral pharmaceutical compositions in pellet or tablet form for reversible proton pump inhibitors for combined use with antimicrobially-active ingredients for the treatment of disorders caused by Helicobacter, wherein the reversible proton pump inhibitor is present at least partly in slow-release form.
DETAILS
Reversible proton pump inhibitors are, for the purpose of the present invention, those active ingredients which reversibly bind to the enzyme responsible for gastric acid secretion, H+ /K+ ATPase. Examples of reversible proton pump inhibitors are enumerated in the previously-noted documents. Examples of reversible proton pump inhibitors are, e.g., 8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (hereinafter B9401-011), 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2 methylimidazo[1,2-a]pyridine, 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine, 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-ethoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-isobutoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-isopropoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine, 8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzyloxy}-2-methylimidazo[1,2-a]pyridine-3-methanol, 8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2-methylimidazo[1,2-a]pyridine-3-methanol, 8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2,3-dimethylimidazo[1,2-a]pyridine, 8-{2-[(2-methoxyethoxy)-carbonylamino]-6-methylbenzyloxy}-2-methylimidazo[1,2-a]pyridine-3-methanol, 8-{2-[(2-methoxyethoxy) carbonylamino]-6-methylbenzyloxy}-2,3-dimethylimidazo[1,2-a]pyridine, 3-hydroxymethyl-2-methyl-8-benzyloxyimidazo-[1,2-a]pyridine, 3-hydroxymethyl-2-trifluoromethyl-8-benzyloxyimidazo-[1,2-a]pyridine, 1,2-dimethyl-3-cyanomethyl-8-benzyloxyimidazo[1,2-a]pyridine, 2-methyl-3-cyanomethyl-8-benzyloxyimidazo[1,2-a]pyridine, 3-butyryl-8-methoxy-4-(2-methylphenylamino)quinoline and 3-butyryl-8-hydroxyethoxy-4-(2-methylphenylamino) quinoline.
Reversible proton pump inhibitors can, in this connection, be present as such, in the form of their salts and/or their solvates (e.g. hydrates), etc. Particularly suitable salts are (because all reversible proton pump inhibitors are substances with a basic reaction) all acid-addition salts. Particular mention may be made of the pharmacologically-acceptable salts of inorganic and organic acids customarily used in pharmaceutical technology, including water-soluble and water-insoluble acid-addition salts with acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid and 3-hydroxy-2-naphthoic acid, the acids being used in the preparation of the salt in a ratio of amounts which are equimolar or different therefrom--depending on whether the acid is mono- or polybasic and depending on the salt required.
Examples of suitable antimicrobially-active ingredients (active against Helicobacter pylori) are enumerated in European Patent Application EP-A-282131. These active ingredients include, for example, bismuth salts (such as bismuth subcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such as nitrofurazone, nitrofurantoin or furazolidone), metronidazole, tinidazole, nimorazole or antibiotics. Examples of antibiotics which may be mentioned in this connection are, arranged according to particular classes of active ingredient: aminoglycosides, such as gentamicin, neomycin, kanamycin, amikacin or streptomycin; macrolides, such as erythromycin, azithromycin, clarithromycin, clindamycin or rifampicin; penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillin or amoxicillin; polypeptides, such as bacitracin or polymyxin; tetracyclines, such as tetracyline, chlorotetracycline, oxytetracycline, minocycline or doxycycline; carbapenems, such as imipenem, loracarbef, meropenem or panipenem; cephalosporins, such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxime proxetil, cefaclor, cefadroxil or cephalothin; gyrase inhibitors, such as ciprofloxacin, norfloxacin, ofloxacin or pefloxacin; or other different antibiotics, such as chloramphenicol. Particularly worthy of mention in this connection is also the combination of a plurality of antimicrobially-active ingredients, for example the combination of a bismuth salt and/or tetracycline with metronidazole, or the combination of amoxicillin or clarithromycin with metronidazole.
Particularly worthy of mention in this connection is also administration of a reversible proton pump inhibitor together with a plurality of antimicrobially-active ingredients, for example with the combination of a bismuth salt and/or tetracycline with metronidazole, or with the combination of amoxicillin or clarithromycin or with metronidazole.
The dosage of the active ingredients depends greatly on the nature of the reversible proton pump inhibitor used and of the antimicrobially-active ingredient(s) used. A typical dosage of a reversible proton pump inhibitor as disclosed, for example, in WO-A-9418199 can be regarded as a daily dose of from about 0.01 to about 20, preferably from 0.05 to 5, and in particular from 0.1 to 1.5, mg/kg of body weight, where appropriate in the form of a plurality of single doses. Penicillins, such as amoxicillin, are administered in a daily dose of from about 5 to 40, preferably from 10 to 20, mg/kg of body weight.
Antimicrobially-active ingredients which may be emphasized are erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline, doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin, of loxacin and pefloxacin.
Clarithromycin and amoxicillin may be mentioned as antimicrobially-active ingredients which should be particularly emphasized.
Combined administration means (for the purpose of the present invention) fixed and, in particular, free combinations, i.e. the slow-release reversible proton pump inhibitor and the antimicrobially-active ingredient are present together in one dosage unit, or slow-release reversible proton pump inhibitor and antimicrobially-active ingredient, which are present in separate dosage units, are administered in direct succession or at a relatively large time interval; a relatively large time interval means within a time span of up to a maximum of 24 hours. For use as separate dosage units, these are preferably made available together in one pack. For example, the two dosage units are packed together in blister packs which are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the times for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
A dosage unit means, in particular, those medicinal dosage forms in which slowing or extending of reversible proton pump inhibitor release is achieved with as few problems as possible. These include, in particular, tablets, coated tablets or pellets, and microtablets in capsules, with the dosage form advantageously being designed so that the two active ingredient components (reversible proton pump inhibitor on the one hand and antimicrobially-active ingredient on the other hand) are released, or made available effectively for the body, in such a way that an optimal active-ingredient profile (and thus action profile) is achieved.
For slowing release, various types and degrees of retarding release may be used to ensure a reversible proton pump inhibitor plasma level which persists as long as possible and is sufficient for raising pH.
The pharmaceutical formulation of the antimicrobially-active ingredient(s) is carried out in a manner which is familiar per se to the skilled worker for the individual active ingredients.
The rapid release of part of the reversible proton pump inhibitor and retarding release of another part is optionally achieved, for example, by layered tablets or multilayer tablets, in which part of the reversible proton pump inhibitor is present in an outer coating in a form without slowing release; this is followed by another coating containing the antimicrobially-active ingredient and then the core with the reversible proton pump inhibitor whose release is slowed in a suitable manner.
The details of how to achieve slowing release are familiar to the skilled worker on the basis of his expert knowledge. The skilled worker is likewise familiar with suitable ancillary substances and vehicles for the required dosage forms (pharmaceutical formulations). Besides solvents, tablet ancillary substances and other active ingredient excipients it is possible to use, for example, tablet-coating compositions, plasticizers, antioxidants, preservatives, dyes, etc. Where incompatibilities between the active ingredients or between the active ingredients and ancillary substances are to be expected, suitable separating layers must be provided where appropriate.
The oral pharmaceutical compositions according to the invention are distinguished from the prior art by controlled release of active ingredients and increased stability.
Besides filler and binder, other ancillary substances, in particular lubricants and nonstick agents, and tablet disintegrants, are used in the manufacture of the tablet cores. A suitable binder is, in particular, polyvinylpyrrolidone in various degrees of polymerization. Examples of lubricants and nonstick agents are higher fatty acids and their alkali-metal and alkaline-earth-metal salts, such as calcium stearate. Suitable tablet disintegrants are, in particular, chemically-inert agents. Preferred tablet disintegrants include cross-linked polyvinylpyrrolidone, crosslinked sodium carboxymethylcelluloses and sodium starch glycolate.
Examples of suitable film polymers, in respect of the water-insoluble release-slowing intermediate layer(s) to be applied to the pellet or tablet core, include ethylcellulose, polyvinyl acetate, Eudragit® RS, Eudragit® RL, etc. The release rate can be controlled not only by incorporating suitable water-soluble pore formers, such as PEG, lactose, mannitol, sorbitol, HPMC, etc., but also by the thickness of the coating layer applied.
The solvents or dispersants used for the release-controlling polymer dispersion are non-aqueous organic solvents, such as alcohols, ketones, halogenated hydrocarbons or mixtures of such solvents.
It is possible in a similar way to use osmotic systems with semipermeable membranes of cellulose acetate, cellulose acetate butyrate or cellulose acetate propionate (as described in U.S. Pat. No. 3,845,770, U.S. Pat. No. 3,916,899, U.S. Pat. No. 4,036,227, U.S. Pat. No. 4,093,708, U.S. Pat. No. 4,096,238, U.S. Pat. No. 4,135,514 and U.S. Pat. No. 4,142,526) to control the release of active ingredients. These can be coated with aqueous dispersions of enteric lacquers without changing the release rate.
Examples of suitable polymers for the enteric coating are methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymer (Eudragit® L) or cellulose derivatives, such as carboxymethylethylcellulose (CMEC, Duodcel), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinyl acetate phthalate, to which it is also possible to add, if desired, plasticizer (such as propylene glycol) and/or other additives and ancillary substances (e.g. buffer base, such as, preferably, aluminum hydroxide; or pigment). The layers are applied in conventional ways using equipment customary for these purposes.
SUSCEPTIBILITY OF COMMERCIAL APPLICATION
The combined use according to the invention of a slow-release reversible proton pump inhibitor with an antimicrobially-active ingredient meets all the requirements for a pharmaceutical product or combination pharmaceutical product for the treatment of gastric disorders attributable to the microbe, Helicobacter pylori. The particular advantages connected with the combined use of the slow-release drug form with an antimicrobially-active ingredient which may be mentioned are: the rapid onset of action with pH values as far as neutral in the lumen of the stomach and in the wall of the stomach and an optimal displaying of the effect of the antimicrobially-active ingredient. The short duration of treatment which can be achieved increases the compliance, which is extremely important for antibiotic treatments.
EXAMPLES
The following formulation examples explain the invention in detail without restricting it.
Example 1
Tablets:
I. Production of Uncoated Core:
______________________________________                                    
a)        B9401-011 (hemimalate)                                          
                           119.8 mg                                       
b)        Sodium carboxymethylstarch                                      
                           21.0 mg                                        
c)        Microcrystalline cellulose                                      
                           21.0 mg                                        
          (e.g.: Avicel PH 101                                            
d)        Maize starch     19.4 mg                                        
e)        Magnesium stearate                                              
                            5.0 mg                                        
                           186.2 mg                                       
______________________________________
a) is mixed with b), c) and part of d). A paste is prepared with the remainder of d). The latter is used for granulation of the powder mixture in a suitable mixer. The granules are dried in a drying oven or fluidized bed. e) is added to the dried granules, and the granules are compressed in a suitable tabletting machine.
II. Release-slowing Layer
______________________________________                                    
f)         Ethylcellulose                                                 
                        9.85 mg                                           
g)         Lactose micronized                                             
                        2.37 mg                                           
h)         Propylene glycol                                               
                        0.98 mg                                           
                        14.00 mg                                          
______________________________________
f) is dissolved in 165 ml of isopropanol. h) is stirred in for a sufficient length of time using a suitable agitator to form a solution (A). g) is suspended in 165 ml of isopropanol using a rotor-stator agitator to form a fine suspension (B). (A) and (B ) are combined.
The tablet cores obtained under I are coated to an adequate layer thickness with the suspension obtained above in suitable apparatus.
Example 2
Tablets:
I. Production of Uncoated Core:
Production of the cores takes place as in Example 1, I.
II. Release-slowing Layer:
______________________________________                                    
f)         Polyvinyl acetate                                              
                        10.38 mg                                          
g)         Lactose micronized                                             
                         2.59 mg                                          
h)         Propylene glycol                                               
                         1.03 mg                                          
                        13.13 mg                                          
______________________________________
f) is dissolved in 150 ml of a 1:1 acetone/chloroform mixture. h) is stirred in for a sufficient length of time, using a suitable agitator to prepare a solution (A).
g) is suspended in 150 ml of a 1:1 acetone/chloroform mixture, using rotor-stator agitator to prepare a fine dispersion (B). (A) and (B) are combined.
The tablet cores obtained under I are coated to a sufficient layer thickness with the thus-obtained dispersion in suitable apparatus.
Example 3
Pellets:
I. Starter Pellets
______________________________________                                    
a)       Sucrose pellets (0.7-0.85 mm)                                    
                           950.0 g                                        
b)       Hydroxypropylmethylcellulose                                     
                           40.0 g                                         
         2910 (USP)                                                       
c)       Propylene glycol  10.0 g                                         
______________________________________
a) is sprayed with an aqueous solution of b) and c) in a fluidized bed (Wurster method).
II. Active Pellets
______________________________________                                    
d)       B9401-011 (Hemimalate)                                           
                           403.0 g                                        
e)       Hydroxypropylmethylcellulose                                     
                           403.0 g                                        
         2910 (USP)                                                       
f)       Propylene glycol  201.5 g                                        
______________________________________
d), e), f) are successively dissolved in 4 liters of purified water and sprayed onto 900 g of the pellets obtained under I in a fluidized bed (Wurster method).
III. Slow-release Pellets
A release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
Example 4
Pellets:
I. Active Pellets
______________________________________                                    
a)        B9401-011 (Hemimalate)                                          
                          403.0 g                                         
b)        Microcrystalline cellulose                                      
                          117.0 g                                         
          (Avicel PH101)                                                  
c)        Na carboxymethylcellulose                                       
                           18.0 g                                         
______________________________________
a) and b) are premixed dry and subsequently moistened to a paste-like consistency with a solution of Na carboxymethylcellulose in water in a conventional kneader or high-speed mixer. The resulting composition is then extruded and shaped into pellets by the extruder/rounder method familiar to the skilled worker. The moistened pellets are dried in suitable equipment (drying oven, fluidized bed, etc.).
III. Slow-release Pellets:
The release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
The invention and its advantages are readily understood from the foregoing description. As is apparent, various changes can be made in the products and methods without departing from the spirit and scope of the invention or sacrificing its material advantages. The products and processes hereinbefore described are merely illustrative of preferred embodiments of the invention.

Claims (18)

What is claimed is:
1. An oral pharmaceutical reversible-proton-pump-inhibitor composition comprising a reversible-proton-pump inhibitor in combination with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter, wherein at least part of the reversible-proton-pump inhibitor is in slow-release form, the composition including an effective amount of polymer to control release of at least part of the reversible-proton-pump inhibitor, whereby onset of action of the antimicrobially-active ingredient takes place significantly faster than on administration thereof with a non-slow-release reversible-proton-pump inhibitor.
2. An oral pharmaceutical composition as claimed in claim 1, wherein the reversible proton pump inhibitor, which is wholly or partly in controlled-release form, is in fixed combination with the antimicrobially-active ingredient in a single dosage unit.
3. An oral pharmaceutical composition as claimed in claim 2, wherein the reversible proton pump inhibitor is in pellet form together with the antimicrobially-active ingredient in a capsule as a dosage unit.
4. An oral pharmaceutical reversible-proton-pump-inhibitor composition comprising a reversible-proton-pump inhibitor in combination with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter and wherein at least part of the reversible-pump-inhibitor is in slow-release form, the reversible-proton-pump inhibitor being together with the antimicrobially-active ingredient in a multilayer tablet.
5. A single package comprising an oral pharmaceutical composition as claimed in claim 1, wherein the reversible proton pump inhibitor and the antimicrobially-active ingredient are in separate dosage units.
6. A single package as claimed in claim 5, wherein the single package is a blister pack which is designed by the relative arrangement of individual components of the dosage units, by inscription and/or by coloring to communicate a dosage regimen to a patient.
7. An oral pharmaceutical reversible-proton-pump-inhibitor composition comprising a reversible-proton-pump inhibitor in combination with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter and wherein at least part of the reversible-proton-pump inhibitor is in slow-release form, the reversible-proton-pump inhibitor being a member selected from group consisting of
8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-di-methylimidazo[1,2-a]pyridine,
3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine,
3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine,
8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2,3-di-methylimidazo[1,2-a]pyridine,
8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,
8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine,
8-(2-ethoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,
8-(2-isobutoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,
8-(2-isopropoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,
8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine,
8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine,
8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzyloxy}-2-methylimidazo[1,2-a]pyridine-3-methanol,
8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2-methylimidazo[1,2-a]pyridine-3-methanol,
8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2,3-dimethylimidazo[1,2-a]pyridine,
8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzyloxy}-2-methylimidazo[1,2-a]pyridine-3-methanol,
8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzyloxy}-2,3-dimethylimidazo[1,2-a]pyridine,
3-hydroxylmethyl-2-methyl-8-benzyoxylimidazo[1,2-a]pyridine,
3-hydroxylmethyl-2-triflouromethyl-8-benzyloxyimidazo[1,2-a]pyridine,
1,2-dimethyl-3-cyanomethyl-8-benzyloxyimidazo[1,2-a]pyridine,
2-methyl-3-cyanomethyl-8-benzyloxyimidazo[1,2-a]pyridine,
3-butyryl-8-methoxy-4-(2-methylphenylamino)quinoline and
3-butyryl-8-hydroxyethoxy-4-(2-methylphenylamino)quinoline,
or a salt thereof.
8. An oral pharmaceutical reversible-proton-pump-inhibitor composition comprising a reversible-proton-pump inhibitor in combination with an antimicbially-active ingredient for treating a disorder caused by Heliobacter and wherein part of the reversible-proton-pump inhibitor is in slow-release form, the reversible-proton-pump inhibitor being
8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-di-methylimidazo[1,2-a]pyridine,
or a salt thereof.
9. A pharmaceutical composition as claimed in claim 1, wherein the antimicrobially-active ingredient is a member selected from the group consisting of bismuth subcitrate, bismuth subsalicylate, nitrofurazone, nitrofurantoin, furazolidone, metronidazole, tinidazole, nimorazole, gentamicin, neomycin, kanamycin, amikacin, streptomycin, erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, penicillin G, penicillin V, ampicillin, mezlocillin, amoxicillin, bacitracin, polymyxin, tetracycline, chlorotetracycline, oxytetracycline, minocycline, doxycycline, imipenem, loracarbef, meropenem, panipenem, cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxime proxetil, cefaclor, cefadroxil, cephalothin, ciprofloxacin, norfloxacin, ofloxacin, pefloxacin and chloramphenicol.
10. A process for the production of an oral pharmaceutical composition in pellet or tablet form for a reversible proton pump inhibitor, as active ingredient, or for combined use thereof with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter, which comprises a) incorporating the active ingredient into a pellet or tablet core, b) applying thereto at least one release-slowing intermediate layer comprising a water-insoluble, release-slowing acidic film former and c) subsequently applying an outer enteric layer which is soluble in the small intestine.
11. A process as claimed in claim 10, wherein the water-insoluble, release-slowing film former for the intermediate layer is applied dissolved or dispersed in a solvent.
12. In a method for treating a disorder caused by Helicobacter with a reversible proton pump inhibitor, the improvement which comprises orally administering the reversible proton pump inhibitor in controlled-release form and also orally administering an antimicrobially-active ingredient to one afflicted with the disorder, whereby the reversible pump inhibitor in slow-release form enhances action of the antimicrobially-active ingredient on Helicobater.
13. A method of claim 12 wherein the reversible proton pump inhibitor and the antimicrobially-active ingredient are administered in direct succession.
14. A method of claim 12 wherein the reversible proton pump inhibitor and the antimicrobially-active ingredient are administered within a time span of up to 24 hours.
15. An oral pharmaceutical reversible-proton-pump-inhibitor composition of claim 1 in pellet or tablet form.
16. A process as claimed in claim 11, wherein the solvent is a non-aqueous organic solvent.
17. An oral pharmaceutical composition as claimed in claim 15, comprising at least one layer controlling release of active ingredient and formed from a water-insoluble, releae-slowing film former.
18. A method of claim 12 wherein the reversible proton pump inhibitor is in controlled-release form.
US08/498,391 1995-07-05 1995-07-05 Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors Expired - Fee Related US6132768A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
US08/498,391 US6132768A (en) 1995-07-05 1995-07-05 Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors
PT96924850T PT841904E (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITIONS WITH DEFERRED LIBERATION OF REVERSIBLE PUMP REVERSIBLE INHIBITORS
SI9630596T SI0841904T1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
DE69626117T DE69626117T2 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITIONS WITH DELAYED RELEASE OF REVERSIBLE PROTON PUMP INHIBITORS
AT96924850T ATE232091T1 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITIONS SUSTAINED RELEASE REVERSIBLE PROTON PUMP INHIBITORS
CA002225628A CA2225628C (en) 1995-07-05 1996-07-02 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
AU65175/96A AU711577B2 (en) 1995-07-05 1996-07-02 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
DK96924850T DK0841904T3 (en) 1995-07-05 1996-07-02 Oral pharmaceutical preparations with delayed release of reversible proton pump inhibitors
PCT/EP1996/002893 WO1997002021A1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
EP96924850A EP0841904B1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
ES96924850T ES2192227T3 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITIONS WITH DELAYED RELEASE OF REVERSIBLE INHIBITORS OF PUMPS OF PROTONS.
JP9504812A JPH11508578A (en) 1995-07-05 1996-07-02 Oral drug with sustained release reversible proton pump inhibitor
HK98112158A HK1010835A1 (en) 1995-07-05 1998-11-20 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
CY0400048A CY2460B1 (en) 1995-07-05 2004-06-11 Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/498,391 US6132768A (en) 1995-07-05 1995-07-05 Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors

Publications (1)

Publication Number Publication Date
US6132768A true US6132768A (en) 2000-10-17

Family

ID=23980899

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/498,391 Expired - Fee Related US6132768A (en) 1995-07-05 1995-07-05 Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors

Country Status (12)

Country Link
US (1) US6132768A (en)
EP (1) EP0841904B1 (en)
JP (1) JPH11508578A (en)
AT (1) ATE232091T1 (en)
AU (1) AU711577B2 (en)
CY (1) CY2460B1 (en)
DE (1) DE69626117T2 (en)
DK (1) DK0841904T3 (en)
ES (1) ES2192227T3 (en)
HK (1) HK1010835A1 (en)
PT (1) PT841904E (en)
WO (1) WO1997002021A1 (en)

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000033755A1 (en) 1998-12-08 2000-06-15 Intuitive Surgical, Inc. Surgical robotic tools, data architecture, and use
US6605303B1 (en) 1997-12-22 2003-08-12 Astrazeneca Ab Oral pharmaceutical extended release dosage form
US6610323B1 (en) 1997-12-22 2003-08-26 Astrazeneca Ab Oral pharmaceutical pulsed release dosage form
US20030211147A1 (en) * 2000-09-29 2003-11-13 Cullen Daniel J. Proton pump inhibitor formulation
US20030228363A1 (en) * 2002-06-07 2003-12-11 Patel Mahendra R. Stabilized pharmaceutical compositons containing benzimidazole compounds
WO2004035090A1 (en) 2002-10-16 2004-04-29 Orexo Ab Gastric acid secretion inhibiting composition
WO2004041244A2 (en) * 2002-10-30 2004-05-21 Pharmacia Corporation Oral extended release tablets and methods of making and using the same
US6740634B1 (en) * 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof
US20040101558A1 (en) * 2000-12-07 2004-05-27 Rango Dietrich Pharmaceutical preparation in the form of a paste comprising an acid-labile active ingredient
US20040131674A1 (en) * 2001-04-18 2004-07-08 Anders Petterson Gastric acid secretion inhibiting composition
US20040146558A1 (en) * 2003-01-28 2004-07-29 Kyowa Pharmaceutical Co., Ltd. Oral enteric-coated preparation
US20040228915A1 (en) * 2003-04-04 2004-11-18 Noack Robert M. Oral extended release compressed tablets of multiparticulates
US20050020620A1 (en) * 2001-09-14 2005-01-27 Hagan Weigl Substituted imidazo[1, 2-a]-5,6,7,8-tetrahydropyridine-8-ones, method for their production and the use thereof for producing imidazo[1,2-a]pyridines
US20050048077A1 (en) * 2002-02-21 2005-03-03 George Sachs Compositions, test kits and methods for detecting helicobacter pylori
US20050048114A1 (en) * 2003-08-29 2005-03-03 Burnside Beth A. Antibiotic product, use and formulation thereof
US20050113418A1 (en) * 1996-06-20 2005-05-26 Christer Cederberg Administration of pharmaceuticals
US20050129761A1 (en) * 2003-10-01 2005-06-16 Wyeth Pantoprazole multiparticulate formulations
US20050181052A1 (en) * 2004-02-17 2005-08-18 Patel Satishkumar A. Lansoprazole microtablets
US20050232992A1 (en) * 2003-09-03 2005-10-20 Agi Therapeutics Limited Proton pump inhibitor formulations, and methods of preparing and using such formulations
US20070154542A1 (en) * 2005-12-30 2007-07-05 Cogentus Pharmaceuticals, Inc. Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors
WO2007115305A2 (en) 2006-04-04 2007-10-11 Cogentus Pharmaceuticals, Inc. Oral dosage forms including an antiplatelet agent and an acid inhibitor
US20090131471A1 (en) * 2007-06-07 2009-05-21 Dynogen Pharmaceuticals, Inc. Compositions useful for treating gastroesophageal reflux disease
US20090274766A1 (en) * 2006-07-25 2009-11-05 Michael Marash Compositions and Methods For Inhibiting Gastric Acide Secretion Using Derivatives of Small Dicarboxylic Acids in Combination with PPI
US20100062064A1 (en) * 2008-09-09 2010-03-11 Astrazeneca Uk Ltd. Method for Delivering A Pharmaceutical Composition to Patient in Need Thereof
US20100247634A1 (en) * 2005-05-11 2010-09-30 Aleksey Kostadinov Compositions and Methods for Inhibiting Gastric Acid Secretion
CN1857220B (en) * 2006-04-04 2010-10-06 济南康泉医药科技有限公司 Slow released antituberculotic preparation
US20110111039A1 (en) * 2005-05-11 2011-05-12 Aleksey Kostadinov Compositions and Methods for Inhibiting Gastric Acid Secretion
US8062672B2 (en) 2003-08-12 2011-11-22 Shionogi Inc. Antibiotic product, use and formulation thereof
US8206741B2 (en) 2001-06-01 2012-06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
US8303988B2 (en) 2000-10-13 2012-11-06 Shionogi Inc. Antifungal once-a-day product, use and formulation thereof
US8313776B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8313775B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US20130096123A1 (en) * 2010-04-14 2013-04-18 Eupharma Pty Ltd Radiation sensitiser compositions
US8425936B2 (en) 2003-07-21 2013-04-23 Shionogi Inc. Antibiotic product, use and formulation thereof
US8460710B2 (en) 2003-09-15 2013-06-11 Shionogi, Inc. Antibiotic product, use and formulation thereof
US8715727B2 (en) 2004-07-02 2014-05-06 Shionogi Inc. Tablet for pulsed delivery
US8758820B2 (en) 2003-08-11 2014-06-24 Shionogi Inc. Robust pellet
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US8889187B2 (en) 2000-02-24 2014-11-18 Shionogi Inc. Once a day amoxicillin product comprising immediate and delayed release dosage forms
US8945621B2 (en) 2009-06-25 2015-02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US11033536B2 (en) * 2017-10-15 2021-06-15 Centre For Digestive Dieases Compositions and methods for treating, ameliorating and preventing H. pylori infections

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981522A (en) * 1995-09-01 1999-11-09 Kaneka Corporation Treatment of disease caused by infection of Helicobacter
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US5840737A (en) 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
ES2237809T3 (en) * 1997-02-28 2005-08-01 Kaneka Corporation CURE MEDICINE FOR THE DISEASE CAUSED BY HELICOBACTER INFECTION.
ES2232015T3 (en) * 1997-07-25 2005-05-16 Altana Pharma Ag INHIBITOR OF PROTON PUMPS IN THERAPEUTIC COMBINATION WITH ANTIBACTERIAL SUBSTANCES.
US5981499A (en) * 1998-02-20 1999-11-09 Atlantic Biomed Corporation Lesion-directed antibiotics in dry dosage forms for the treatment of shallow ulcers of the oral mucosa
WO2000050037A1 (en) * 1999-02-26 2000-08-31 Nitromed, Inc. Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US6248718B1 (en) 1999-08-18 2001-06-19 Atlantic Biomed Corporation Lesion-directed dry dosage forms of antibacterial agents for the treatment of acute mucosal infections of the oral cavity
EP1210950B1 (en) * 2000-12-04 2005-10-19 New Pharma Research Sweden AB Composition against Coccidiosis
JP2002234842A (en) * 2001-02-09 2002-08-23 Kyowa Yakuhin Kogyo Kk Oral enteric pharmaceutical preparation
EP1534278A4 (en) 2002-08-01 2006-09-06 Nitromed Inc Nitrosated proton pump inhibitors, compositions and methods of use
BR0300882A (en) * 2003-04-09 2005-05-10 Cmax Otimizacao De Resultados Pharmaceutical compositions, method and use of formulation for treatment and prevention of infections associated with helicobacter pylori in mammals and humans
CL2004000983A1 (en) * 2003-05-08 2005-03-04 Altana Pharma Ag ORAL PHARMACEUTICAL COMPOSITION IN THE FORM OF A TABLET THAT INCLUDES DIHYDRATED MAGNETIC PANTOPRAZOL, WHERE THE TABLET FORM IS COMPOSED BY A NUCLEUS, A MIDDLE COAT AND AN OUTER LAYER; AND USE OF PHARMACEUTICAL COMPOSITION IN ULCERAS AND
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
KR100581967B1 (en) * 2003-12-18 2006-05-22 한국유나이티드제약 주식회사 Double pellet formulation of proton pump inhibitors and clarithromycin for the treatment of gastrointestinal ulcer, and method for producing the same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
WO2006037766A1 (en) * 2004-10-05 2006-04-13 Altana Pharma Ag Oral pharmaceutical preparation comprising a proton pump antagonist and a basic excipient
EP1803450A1 (en) 2006-01-03 2007-07-04 Ferrer Internacional, S.A. Pharmaceutical compositions for the eradication of helicobacter pylori

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3456049A (en) * 1965-05-25 1969-07-15 Ciba Geigy Corp Gradual-release tablet
US4464372A (en) * 1982-08-16 1984-08-07 Schering Corporation Imidazo[1,2-b]pyridazines
US4692337A (en) * 1983-04-09 1987-09-08 Nikken Chemicals Co., Ltd. Sustained release pharmaceutical tablet of theophylline and production process thereof
US4994276A (en) * 1988-09-19 1991-02-19 Edward Mendell Co., Inc. Directly compressible sustained release excipient
US5041442A (en) * 1990-07-31 1991-08-20 Syntex (U.S.A.) Inc. Pyrrolo(1,2-a)pyrazines as inhibitors of gastric acid secretion
US5409903A (en) * 1992-02-18 1995-04-25 Urecap Corporation Method and compositions for the treatment of H. pylori and dermatitis
US5476669A (en) * 1987-10-12 1995-12-19 Examed Australia Pty. Ltd. Method for treatment of gastro intestinal disorders
US5599794A (en) * 1992-04-24 1997-02-04 Aktiebolaget Astra Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL108520A (en) * 1993-02-15 1997-09-30 Byk Gulden Lomberg Chem Fab 2, 3, 8-TRISUBSTITUTED IMIDAZO £1, 2-a| PYRIDINE DERIVATIVES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3456049A (en) * 1965-05-25 1969-07-15 Ciba Geigy Corp Gradual-release tablet
US4464372A (en) * 1982-08-16 1984-08-07 Schering Corporation Imidazo[1,2-b]pyridazines
US4692337A (en) * 1983-04-09 1987-09-08 Nikken Chemicals Co., Ltd. Sustained release pharmaceutical tablet of theophylline and production process thereof
US5476669A (en) * 1987-10-12 1995-12-19 Examed Australia Pty. Ltd. Method for treatment of gastro intestinal disorders
US4994276A (en) * 1988-09-19 1991-02-19 Edward Mendell Co., Inc. Directly compressible sustained release excipient
US5041442A (en) * 1990-07-31 1991-08-20 Syntex (U.S.A.) Inc. Pyrrolo(1,2-a)pyrazines as inhibitors of gastric acid secretion
US5409903A (en) * 1992-02-18 1995-04-25 Urecap Corporation Method and compositions for the treatment of H. pylori and dermatitis
US5599794A (en) * 1992-04-24 1997-02-04 Aktiebolaget Astra Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic

Cited By (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050113418A1 (en) * 1996-06-20 2005-05-26 Christer Cederberg Administration of pharmaceuticals
US6605303B1 (en) 1997-12-22 2003-08-12 Astrazeneca Ab Oral pharmaceutical extended release dosage form
US6610323B1 (en) 1997-12-22 2003-08-26 Astrazeneca Ab Oral pharmaceutical pulsed release dosage form
US20050025826A1 (en) * 1998-01-16 2005-02-03 Akira Saikawa Sustained release compositions, process for producing the same and utilization thereof
US6740634B1 (en) * 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof
US7388032B2 (en) 1998-01-16 2008-06-17 Takeda Pharmaceutical Company Limited Sustained release compositions, process for producing the same and utilization thereof
WO2000033755A1 (en) 1998-12-08 2000-06-15 Intuitive Surgical, Inc. Surgical robotic tools, data architecture, and use
US8889187B2 (en) 2000-02-24 2014-11-18 Shionogi Inc. Once a day amoxicillin product comprising immediate and delayed release dosage forms
US20030211147A1 (en) * 2000-09-29 2003-11-13 Cullen Daniel J. Proton pump inhibitor formulation
US8303988B2 (en) 2000-10-13 2012-11-06 Shionogi Inc. Antifungal once-a-day product, use and formulation thereof
US20040101558A1 (en) * 2000-12-07 2004-05-27 Rango Dietrich Pharmaceutical preparation in the form of a paste comprising an acid-labile active ingredient
US7988999B2 (en) * 2000-12-07 2011-08-02 Nycomed Gmbh Pharmaceutical preparation in the form of a paste comprising an acid-labile active ingredient
US20040131674A1 (en) * 2001-04-18 2004-07-08 Anders Petterson Gastric acid secretion inhibiting composition
US20110104264A1 (en) * 2001-04-18 2011-05-05 Orexo Ab Gastric acid secretion inhibiting composition
US20080031941A1 (en) * 2001-04-18 2008-02-07 Orexo Ab Gastric acid secretion inhibiting composition
US7815940B2 (en) 2001-04-18 2010-10-19 Orexo Ab Gastric acid secretion inhibiting composition
US9364439B2 (en) 2001-06-01 2016-06-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8557285B2 (en) 2001-06-01 2013-10-15 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8206741B2 (en) 2001-06-01 2012-06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9345695B2 (en) 2001-06-01 2016-05-24 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9198888B2 (en) 2001-06-01 2015-12-01 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9707181B2 (en) 2001-06-01 2017-07-18 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8852636B2 (en) 2001-06-01 2014-10-07 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9161920B2 (en) 2001-06-01 2015-10-20 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US8858996B2 (en) 2001-06-01 2014-10-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDS
US8865190B2 (en) 2001-06-01 2014-10-21 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US7196196B2 (en) 2001-09-14 2007-03-27 Basf Aktiengesellschaft Substituted imidazo[1, 2-a]-5,6,7,8-tetrahydropyridine-8-ones, method for their production and the use thereof for producing imidazo[1,2-a]pyridines
US20050020620A1 (en) * 2001-09-14 2005-01-27 Hagan Weigl Substituted imidazo[1, 2-a]-5,6,7,8-tetrahydropyridine-8-ones, method for their production and the use thereof for producing imidazo[1,2-a]pyridines
US20050048077A1 (en) * 2002-02-21 2005-03-03 George Sachs Compositions, test kits and methods for detecting helicobacter pylori
US20030228363A1 (en) * 2002-06-07 2003-12-11 Patel Mahendra R. Stabilized pharmaceutical compositons containing benzimidazole compounds
US20060115530A1 (en) * 2002-10-16 2006-06-01 Anders Pettersson Gastric acid secretion inhibiting composition
EP2258341A2 (en) 2002-10-16 2010-12-08 Orexo AB Gastric acid secretion inhibiting composition
WO2004035090A1 (en) 2002-10-16 2004-04-29 Orexo Ab Gastric acid secretion inhibiting composition
US7785626B2 (en) 2002-10-16 2010-08-31 Orexo Ab Gastric acid secretion inhibiting composition
US20070031497A1 (en) * 2002-10-16 2007-02-08 Orexo Ab Gastric acid secretion inhibiting composition
US20100151013A1 (en) * 2002-10-16 2010-06-17 Orexo Ab Gastric acid secretion inhibiting composition
US7771747B2 (en) 2002-10-16 2010-08-10 Orexo Ab Gastric acid secretion inhibiting composition
WO2004041244A3 (en) * 2002-10-30 2004-07-15 Pharmacia Corp Oral extended release tablets and methods of making and using the same
WO2004041244A2 (en) * 2002-10-30 2004-05-21 Pharmacia Corporation Oral extended release tablets and methods of making and using the same
US20040146558A1 (en) * 2003-01-28 2004-07-29 Kyowa Pharmaceutical Co., Ltd. Oral enteric-coated preparation
US20040228915A1 (en) * 2003-04-04 2004-11-18 Noack Robert M. Oral extended release compressed tablets of multiparticulates
US8313776B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8313775B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8425936B2 (en) 2003-07-21 2013-04-23 Shionogi Inc. Antibiotic product, use and formulation thereof
US8758820B2 (en) 2003-08-11 2014-06-24 Shionogi Inc. Robust pellet
US9144548B2 (en) 2003-08-12 2015-09-29 Shionogi Inc. Antibiotic product, use and formulation thereof
US8062672B2 (en) 2003-08-12 2011-11-22 Shionogi Inc. Antibiotic product, use and formulation thereof
US8246996B2 (en) 2003-08-29 2012-08-21 Shionogi Inc. Antibiotic product, use and formulation thereof
US20050048114A1 (en) * 2003-08-29 2005-03-03 Burnside Beth A. Antibiotic product, use and formulation thereof
US20050232992A1 (en) * 2003-09-03 2005-10-20 Agi Therapeutics Limited Proton pump inhibitor formulations, and methods of preparing and using such formulations
US8460710B2 (en) 2003-09-15 2013-06-11 Shionogi, Inc. Antibiotic product, use and formulation thereof
US20070196444A1 (en) * 2003-10-01 2007-08-23 Wyeth Pantoprazole multiparticulate formulations
US7544370B2 (en) 2003-10-01 2009-06-09 Wyeth Pantoprazole multiparticulate formulations
US20050129761A1 (en) * 2003-10-01 2005-06-16 Wyeth Pantoprazole multiparticulate formulations
US20070042033A1 (en) * 2003-10-01 2007-02-22 Wyeth Pantoprazole multiparticulate formulations
US7553498B2 (en) 2003-10-01 2009-06-30 Wyeth Pantoprazole multiparticulate formulations
US20070196443A1 (en) * 2003-10-01 2007-08-23 Wyeth Pantoprazole multiparticulate formulations
US7838027B2 (en) 2003-10-01 2010-11-23 Wyeth Llc Pantoprazole multiparticulate formulations
US7550153B2 (en) 2003-10-01 2009-06-23 Wyeth Pantoprazole multiparticulate formulations
US20050181052A1 (en) * 2004-02-17 2005-08-18 Patel Satishkumar A. Lansoprazole microtablets
US8715727B2 (en) 2004-07-02 2014-05-06 Shionogi Inc. Tablet for pulsed delivery
US9132082B2 (en) 2005-05-11 2015-09-15 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
US20110111039A1 (en) * 2005-05-11 2011-05-12 Aleksey Kostadinov Compositions and Methods for Inhibiting Gastric Acid Secretion
US9370481B2 (en) * 2005-05-11 2016-06-21 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
US9278080B2 (en) 2005-05-11 2016-03-08 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
US20110250268A1 (en) * 2005-05-11 2011-10-13 Aleksey Kostadinov Compositions and Methods for Inhibiting Gastric Acid Secretion
US20100247634A1 (en) * 2005-05-11 2010-09-30 Aleksey Kostadinov Compositions and Methods for Inhibiting Gastric Acid Secretion
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US20070154542A1 (en) * 2005-12-30 2007-07-05 Cogentus Pharmaceuticals, Inc. Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors
CN1857220B (en) * 2006-04-04 2010-10-06 济南康泉医药科技有限公司 Slow released antituberculotic preparation
WO2007115305A2 (en) 2006-04-04 2007-10-11 Cogentus Pharmaceuticals, Inc. Oral dosage forms including an antiplatelet agent and an acid inhibitor
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
US20090274766A1 (en) * 2006-07-25 2009-11-05 Michael Marash Compositions and Methods For Inhibiting Gastric Acide Secretion Using Derivatives of Small Dicarboxylic Acids in Combination with PPI
US9233092B2 (en) 2006-07-25 2016-01-12 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion using derivatives of small dicarboxylic acids in combination with PPI
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US20090131471A1 (en) * 2007-06-07 2009-05-21 Dynogen Pharmaceuticals, Inc. Compositions useful for treating gastroesophageal reflux disease
US20100062064A1 (en) * 2008-09-09 2010-03-11 Astrazeneca Uk Ltd. Method for Delivering A Pharmaceutical Composition to Patient in Need Thereof
US9393208B2 (en) 2008-09-09 2016-07-19 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9220698B2 (en) 2008-09-09 2015-12-29 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9801824B2 (en) 2008-09-09 2017-10-31 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US8945621B2 (en) 2009-06-25 2015-02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer
US20130096123A1 (en) * 2010-04-14 2013-04-18 Eupharma Pty Ltd Radiation sensitiser compositions
US9539214B2 (en) 2011-12-28 2017-01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US9987231B2 (en) 2011-12-28 2018-06-05 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US10603283B2 (en) 2011-12-28 2020-03-31 Genus Lifesciences, Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US11033536B2 (en) * 2017-10-15 2021-06-15 Centre For Digestive Dieases Compositions and methods for treating, ameliorating and preventing H. pylori infections
US11833140B2 (en) 2017-10-15 2023-12-05 Centre For Digestive Diseases Compositions and methods for treating, ameliorating and preventing H. pylori infections

Also Published As

Publication number Publication date
DK0841904T3 (en) 2003-05-26
EP0841904A1 (en) 1998-05-20
CY2460B1 (en) 2005-06-03
DE69626117T2 (en) 2003-10-30
JPH11508578A (en) 1999-07-27
DE69626117D1 (en) 2003-03-13
ATE232091T1 (en) 2003-02-15
EP0841904B1 (en) 2003-02-05
WO1997002021A1 (en) 1997-01-23
AU711577B2 (en) 1999-10-14
ES2192227T3 (en) 2003-10-01
PT841904E (en) 2003-06-30
AU6517596A (en) 1997-02-05
HK1010835A1 (en) 1999-07-02

Similar Documents

Publication Publication Date Title
US6132768A (en) Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors
US6274173B1 (en) Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
CA2186039C (en) New oral pharmaceutical dosage form
EP1746980B1 (en) Pharmaceutical dosage form comprising pellets as well as its manufacturing process
AU2010200905B2 (en) Dosage form containing pantoprazole as active ingredient
MXPA05001538A (en) Endoscope sleeve dispenser.
CZ283684B6 (en) Pharmaceutical system treated for providing therapeutically active concentration level of 7-dimethylamino-6-deoxy-6-demethyltetracycline or non-toxic acid addition salt thereof in blood for a prolonged time interval and process for preparing such therapeutical system
MXPA96004354A (en) New form of pharmaceutical dosage or
KR20180001586A (en) Pharmaceutical formulations containing rifaximin, processes for their obtainment and method of treating intestinal disease
US20080050428A1 (en) Oral Pharmaceutical Preparation Comprising a Proton Pump Antagonist and a Basic Excipient
US20120164233A1 (en) Pulsatile release pharmaceutical formulation of dexlansoprazole
US20060204568A1 (en) Oral pharmaceutical preparation for proton pump antagonists
CA2225628C (en) Oral pharmaceutical compositions with delayed release of reversible proton pump inhibitors
JP2004520358A (en) Sustained-release pharmaceutical compositions containing beta-lactam antibiotics with improved therapeutic efficacy
MXPA05001559A (en) Isosorbide mononitrate compositions and methods of their use.
EP1785135A1 (en) New stabilized galenic formulations comprising lansoprazole and their preparation
DE10317023A1 (en) Oral dosage form useful in the treatment and prevention of gastrointestinal disorders e.g. inflammatory disorders and lesions such as gastric ulcer comprises proton pump inhibitor and basic excipients
CA2563162C (en) Dosage form containing pantoprazole as active ingredient
US20230248673A1 (en) Novel multiparticulate pharmaceutical composition of tamsulosin and solifenacin

Legal Events

Date Code Title Description
AS Assignment

Owner name: BYK GULDEN CHEMISCHE FABRIK GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SACHS, GEORGE;DIETRICH, RANGO;REEL/FRAME:007620/0392;SIGNING DATES FROM 19950619 TO 19950628

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

AS Assignment

Owner name: ALTANA PHARMA AG, GERMANY

Free format text: CHANGE OF NAME;ASSIGNOR:BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH;REEL/FRAME:013128/0431

Effective date: 20020701

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20121017